Posts tagged ‘Clinical Cancer Research’

There has been a lot of negative publicity around Dendreon and sipuleucel-T (Provenge) recently, and the lack of a clear mechanism of action remains a concern to many.

Irrespective of the company’s commercial performance, sipuleucel-T remains an FDA approved therapeutic cancer vaccine that provides a benefit to some patients. It provided a proof-of-concept that immunotherapy can offer a survival advantage, albeit for a median of 4.1 months in asymptomatic advanced prostate cancer.

Dendreon is learning the hard way the failings in its commercial strategy, and no doubt these will be absorbed by others with other therapeutic vaccines in development.

Researchers from the National Cancer Institute (NCI) published data from a small pilot trial showing a clinical response to a poxviral vaccine (PANVAC) in metastatic breast cancer and ovarian cancer patients.

Twenty six patients were in involved in the pilot NCI trial with PANVAC, a recombinant poxviral vaccine expressing the tumor-associated antigens (TAA), carcinoembryonic antigen (CEA) and mucin-1 (MUC-1).

The results showed a median overall survival of 13.7 months in the 12 breast cancer patients with four patients having stable disease, and one patient on study for 37 months. One patient had a 17% reduction in mediastinal mass.

This is promising early stage data in very sick patients. Mahsa Mohebtash and colleagues conclude in their paper that:

“Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted.”

Immunotherapy holds a lot of promise. Research suggests that cancer vaccines once they have provoked a response may improve a patients’ response to subsequent therapies through enhanced T-cell response.

The NCI researchers in their paper noted that time to progression and tumor shrinkage may not be good endpoints for evaluating immunotherapies given that it can take a few months for the optimal result after vaccination and there is often little impact on the tumor size, as judged by classical RECIST measurement.

Instead, overall survival (OS) should be considered a more relevant endpoint. Sipuleucel-T failed to show a benefit in progression free survival (PFS), but did show an impact on OS. In prostate cancer, OS remains the gold standard for regulatory approval, which is why Exelixis recently took a hit for not making this the primary endpoint in their phase III trial (306) for cabozantinib (XL184).

There are several challenges to consider with vaccine therapies:

How do we identify upfront which patients are most likely to respond to the vaccine?

The ideal setting is likely to be adjuvant rather than metastatic disease, but these trials will take a very long time and significant funding to come to fruition.

Cancer vaccines may allow some patients to live longer, but they have yet to show any meaningful benefit in other clinical measures such as bone pain, symptoms etc.

There are fewer side effects, but how do we evaluate how well patients are doing without clinically validated surrogate markers to aid in assessment?

This early research with a vaccine in breast and ovarian cancer, albeit on a very small number of patients, adds further support to the notion that vaccines may offer treatment benefits in the future.

We still, however, have a long way to go in understanding how best to use immunotherapy effectively and incorporate it into clinical treatment guidelines. We should also be wary of false hope and hype – I look forward to following the progress of PANVAC going forward.

One of the challenges with cancer is being able to detect the disease early enough for effective treatment. The staging or progression of the cancer at time of diagnosis is correlated with 5 year overall survival (OS) rates. Biomarkers that may be expressed by a cancer are, therefore, potentially useful for diagnosis and monitoring of treatment.

There is an ongoing debate about the effectiveness of prostate specific antigen (PSA) as a biomarker for early detection of Prostate Cancer (PC). As Sally Church on Pharma Strategy Blog discusses, PSA measurements can offer false positives and up to 75% of men have a negative biopsy. There is clearly a need for alternatives to PSA measurements.

In the March 1, 2011 online edition of Clinical Cancer Research(a journal of the American Association for Cancer Research, AACR), Richard Morgan and colleagues from the Postgraduate Medical School at the University of Surrey in Guildford, assessed the potential of the Engrailed-2 (EN2) protein as a prognostic biomarker for PC.

Their research found that EN2 is secreted into the urine of men with PC (92%, n=104), but does not appear in the urine of those without PC (0%, n=11). Presence of EN2 in the urine showed a 66% sensitivity for the detection of PC without a digital rectal exam (DRE) when compared to biopsy findings of those with confirmed PC (54 of 82 men). The specificity of the test is almost 90%, i.e. it can pick out men with prostate cancer versus those without cancer.

Interestingly, there was no correlation between serum PSA levels and the presence or absence of EN2. EN2 is measured in small quantities of unprocessed urine (100μl) by means of a simple enzymatic assay.

The investigators state in their paper that a multicenter clinical trial is planned to investigate whether EN2 measurements can be used as a tool for monitoring disease progression after hormonal treatment, radiotherapy or surgery.

However, despite the promising preliminary results in this paper, it is still too early to say whether EN2 will evolve into a clinically useful predictive biomarker for PC. The fact that EN2 was secreted in patients with non-PSA secreting PC, raises the possibility that it might have a diagnostic role to play in combination with other biomarkers.

EN2 has also been shown to be an oncogene in breast cancer, so it will be interesting to see if there is any further information presented at the forthcoming AACR annual meeting from April 2 to 6 in Orlando.